EP2360152B1 - Deux types de forme cristalline de pinocembrine : a et b, leur préparation et leur utilisation pour la fabrication de compositions pharmaceutiques - Google Patents

Deux types de forme cristalline de pinocembrine : a et b, leur préparation et leur utilisation pour la fabrication de compositions pharmaceutiques Download PDF

Info

Publication number
EP2360152B1
EP2360152B1 EP08878072.1A EP08878072A EP2360152B1 EP 2360152 B1 EP2360152 B1 EP 2360152B1 EP 08878072 A EP08878072 A EP 08878072A EP 2360152 B1 EP2360152 B1 EP 2360152B1
Authority
EP
European Patent Office
Prior art keywords
pinocembrin
crystalline form
crystalline
peak
crystal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP08878072.1A
Other languages
German (de)
English (en)
Other versions
EP2360152A4 (fr
EP2360152B8 (fr
EP2360152A1 (fr
Inventor
Guanhua Du
Yang LV
Song Wu
Ke Wang
Ying Chang
Zhihong Yang
Yuanfeng Tong
Mei Gao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Original Assignee
Institute of Materia Medica of CAMS
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS, CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd filed Critical Institute of Materia Medica of CAMS
Publication of EP2360152A1 publication Critical patent/EP2360152A1/fr
Publication of EP2360152A4 publication Critical patent/EP2360152A4/fr
Application granted granted Critical
Publication of EP2360152B1 publication Critical patent/EP2360152B1/fr
Publication of EP2360152B8 publication Critical patent/EP2360152B8/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to two crystalline forms of the compound pinocembrin, and active pharmaceutical ingredients, pharmaceutical compositions and dosage forms containing the two crystalline forms of pinocembrin, and the use thereof for manufacture of pharmaceutical compositions and treating diseases, and the method for preparing the two crystalline forms of pinocembrin.
  • Pinocembrin (chemical name: 5,'7-dihydroxy-2-phenyl-4-chromanone) is a flavone compound, widely found in the nature. Its chemical structure is as below: exiting in 1-isomer, d-isomer, 1-isomer- or d-isomer-enriched mixture, and racemate.
  • pinocembrin had strong bacteriostasis, antivirus, and antifungal activities.
  • honey a Chinese traditional health care food
  • So eating honey sugar frequently is not only harmless to the teeth, but also can sterilize the oral cavity, for example, relieving oral ulcer and accelerating wound healing.
  • Chinese Patent CN1695608A titled "Use of pinocembrin for manufacture of pharmaceutical compositions for preventing and treating diseases related to nerve cell injury" [1] , disclosed the use of pinocembrin for manufacture of pharmaceutical compositions for preventing or treating diseases related to cerebral ischemia, sequelae of cerebral ischemia, nerve cell injury and function alteration.
  • pinocembrin had two different crystalline forms ⁇ and ⁇ , and the inventors developed the preparations thereof.
  • the inventors also found that there was a significant difference between the two crystalline forms in the uptake by organism, wherein the uptake rate of ⁇ crystalline form was greater than that of ⁇ crystalline form, for example, the uptake rate of ⁇ crystalline form can be 2 times or more greater than that of ⁇ crystalline from.
  • the biological activities thereof in medicament therapy are different due to differences in drug blood concentrations.
  • One embodiment of the present invention provides ⁇ crystalline form, or the mixture of ⁇ crystalline form and ⁇ crystalline form in different proportions, with respect to pinocembrin.
  • these crystalline forms or the mixture thereof contains no crystal water or other organic solvents.
  • One embodiment of the present invention provides the method for preparing from ⁇ crystalline form the ⁇ crystalline form, or the mixture of ⁇ crystalline form and ⁇ crystalline form of pinocembrin in different proportions.
  • One embodiment of the present invention provides a pharmaceutical composition comprising pure ⁇ crystalline form, or the mixture of ⁇ crystalline form and ⁇ crystalline form of pinocembrin in different proportions.
  • the pharmaceutical composition can also comprise one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers There is no limitation on the pharmaceutically acceptable carriers, provided that they are suitable for formulation and would not substantially affect the effect of pinocembrin crystalline form of the present invention.
  • dosage forms comprising the pinocembrin ⁇ crystalline form solid.
  • dosage forms can be tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations and the like.
  • One embodiment of the present invention provides use of the crystalline forms solid of pinocembrin, including ⁇ crystalline form, ⁇ crystalline form or the mixture of ⁇ crystalline form and ⁇ crystalline from in different proporations, for bringing about difference of drug uptake in treatment.
  • One embodiment of the present invention relates to the use of ⁇ crystalline form, or the mixture of ⁇ crystalline form and ⁇ crystalline form of pinocembrin in different proportions in the manufacture of a medicament for treating diseases related to cerebral ischemia or a medicament for preventing diseases related to cerebral ischemia by protecting neurovascular unit function.
  • One embodiment of the present invention provides the use of pinocembrin for protecting neurovascular unit function in the treatment of diseases related to cerebral ischemia, and for improving the blood concentration in an organism due to the crystal form effect.
  • Fig. 1 is an illustration showing the relative configuration of the molecule
  • Fig. 2 is an illustration showing the stereo-structure projection of the molecule
  • Fig. 3 is an illustration showing the unit cell stacking of the molecule along the a axis. Table 1 shows atomic coordinate parameters and equivalent temperature factors.
  • Table 2 shows bond length values of bonding atoms.
  • Table 3 shows bond angle values of bonding atoms. As some carbon atoms of B ring adopt a disordered orientation state, the four atoms of C 2' , C 3' , C 5' and C 6' occupy two positions, with an occupancy rate of 0.5 respectively.
  • Powder (polycrystal) X-ray diffraction (CuK ⁇ radiation) was performed on the ⁇ crystalline form solid of pinocembrin, and the diffraction peak locations: 2-Theta value (°) or d value ( ⁇ ), and the relative strength of diffraction peak: peak height value (Height%) or peak area value (Area%) show the following characteristics (see Table 4, Fig. 4).
  • ⁇ crystalline form solid of pinocembrin when analyzed by DSC, shows a decalescence transition temperature of about 206°C (see Fig. 5 ).
  • IR analysis with KBr pellet was performed on ⁇ crystalline form solid of pinocembrin (see Fig. 6 ).
  • the characteristic peaks were as follows: 3090.6, 3011.6, 2889.1, 2747.4, 2636.2, 1631.5, 1602.5, 1584.3, 1487.7, 1466.2, 1454.5, 1435.6, 1354.9, 1302.4, 1257.0, 1217.0, 1168.2, 1088.6, 1064.9, 1028.0, 1014.6, 1001.3, 975.8, 918.0, 887.7, 861.8, 825.9, 789.9, 766.4, 715.2, 698.1, 663.7, 646.7, 620.3, 587.3, 574.9, 560.5, 526.9 and 487.9cm -1 , wherein the peaks of 2891.1, 2747.4, 2636.2, 1631.5 and 1354.9 cm -1 were the main characteristic peaks of ⁇ crystalline form solid of pinocembrin.
  • ⁇ crystalline form solid of pinocembrin when analyzed by DSC, shows a decalescence transition temperature of about 204°C (see Fig. 8 ).
  • IR analysis with KBr pellet was performed on ⁇ crystalline form solid of pinocembrin according to an embodiment of the present invention (see Fig. 9 ).
  • the characteristic peaks were as follows: 3090.8, 2890.0, 2748.9, 2638.3, 1633.5, 1602.9, 1585.0, 1487.9, 1466.1, 1454.3, 1344.4, 1302.7, 1216.7, 1168.2, 1088.4, 1065.5, 1028.8, 1014.3, 1001.5, 975.8, 917.8, 888.2, 861.8, 826.6, 789.1, 766.6, 741.1, 715.4, 698.0, 663.7, 646.0, 620.5, 587.9, 574.8, 560.9, 527.2 and 488.4cm -1 , wherein the peaks of 2890.0. 2748.9, 2638.3, 1633.5 and 1344.4 cm -1 were the main characteristic peaks of ⁇ crystalline form solid of pinocembrin.
  • a solvent selected from the group consisting of methanol, ethanol, chloroform, acetone, ethyl acetate, n-butanol, isopropanol, acetonitrile, THF, dioxane, 95% ethanol, glacial acetic acid, formic acid, ether, dichloromethane, toluene, benzene, n-hexane, cyclohexane, dioxane, DMF, petroleum ether, ammonia, n-propanol, or a mixture thereof, then,
  • Pure ⁇ crystalline form, pure ⁇ crystalline form or the mixture of ⁇ and crystalline forms of pinocembrin in any proportion according to the present invention have an effect on treating diseases related to cerebral ischemia or preventing diseases related to cerebral ischemia by protecting neurovascular unit function.
  • bioavailability of pure ⁇ crystalline form is more than 2 times higher than that of ⁇ crystalline form.
  • bioavailability thereof can vary, dependent on different contents of ⁇ crystalline form.
  • daily dosage is 5 ⁇ 250 mg, based on pinocembrin crystalline forms solid.
  • Preparations include tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations and the like.
  • Example 1 Method 1 for preparing a sample of ⁇ crystalline form of pinocembrin
  • Powder (polycrystal) X-ray diffraction (CuK ⁇ radiation) was performed on the obtained crystalline.
  • the characteristic peak values of the diffraction peak location: 2-Theta value (°) or d value ( ⁇ ) and the relative strength of diffraction peak: peak height value (Height%) or peak area value (Area%) were shown in Table 4, and the obtained trace was shown in Fig. 4 .
  • IR analysis with KBr pellet was performed on the crystalline obtained, and the characteristic peaks were as follows: 3090.6, 3011.6, 2889.1, 2747.4, 2636.2, 1631.5, 1602.5, 1584.3, 1487.7, 1466.2, 1454.5, 1435.6, 1354.9, 1302.4, 1257.0, 1217.0, 1168.2, 1088.6, 1064.9, 1028.0, 1014.6, 1001.3, 975.8, 918.0, 887.7, 861.8, 825.9, 789.9, 766.4, 715.2, 698.1, 663.7, 646.7, 620.3, 587.3, 574.9, 560.5, 526.9 and 487.9cm -1 .
  • Example 11 Method 11 for preparing the sample of ⁇ crystalline form of pinocembrin
  • Example 17 Method 1 for preparing a sample of ⁇ crystalline form of pinocembrin:
  • Powder (polycrystal) X-ray diffraction (CuK ⁇ radiation) was performed on the obtained crystalline.
  • IR analysis with KBr pellet was performed on the crystalline obtained, and the characteristic peaks were as follows: 3090.8, 2890.0, 2748.9, 2638.3, 1633.5, 1602.9, 1585.0, 1487.9, 1466.1, 1454.3, 1344.4, 1302.7, 1216.7, 1168.2, 1088.4, 1065.5, 1028.8, 1014.3, 1001.5, 975.8, 917.8, 888.2, 861.8, 826.6, 789.1, 766.6, 741.1, 715.4, 698.0, 663.7, 646.0, 620.5, 587.9, 574.8, 560.9, 527.2 and 488.4cm -1 .
  • Example 18 Method 2 for preparing ⁇ crystalline form of pinocembrin
  • Example 19 Method 3 for preparing a sample of ⁇ crystalline form of pinocembrin
  • Example 18 Except that pyridine was used as the solvent, the same preparation method as that of Example 18 was used, and 8.8g white crystalline was obtained (purity: 98.6%, detected by HPLC) in a recovery of 88.0%. Powder X-ray diffraction, DSC and IR analysis were performed on the obtained crystalline, and the results showed that the crystalline form obtained was ⁇ crystalline form of pinocembrin.
  • the detailed preparation method was as follows: mixing the excipients with pinocembrin evenly, then adding appropriate amount of 1% sodium hydroxymethyl cellulose solution to make a dough. The dough was screened to obtain granules. The wet granules were dried and sieved. Then magnesium stearate and talc powder were added and mixed evenly, and the product was obtained by tabletting.
  • the detailed preparation method was as follows: mixing the excipients with pinocembrin evenly, then appropriate amount of 1% sodium hydroxymethyl cellulose solution was added to make wet granules, the wet granules were dried and sieved. Then magnesium stearate was added and mixed evenly, and the product was obtained by filling the mixture above into empty capsules. Alternatively, without granulation, the product was obtained by filling the excipients and pinocembrin into empty capsules directly, after they were mixed evenly and sieved.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Vascular Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Pyrane Compounds (AREA)

Claims (13)

  1. Une forme β-cristalline de pinocembrine racémique dont la formule est (I) :
    Figure imgb0006
     caractérisée en ce que, lorsqu'on l'analyse par diffractométrie de rayons X sur échantillon polycristallin (rayonnement CuKα), la positions des pics de diffraction en 2-Theta (°) ou en d (Å), et l'intensités relative des pics de diffraction en hauteur (Hauteur%) ou en zone de pic (Zone%), présentent les caractéristiques suivantes : Pic 2-Theta d(Å) Hauteur % Zone % Pic 2-Theta d(Å) Hauteur % Zone % 1 7.33 12.06 100.0 66.5 14 29.51 3.02 1.6 0.3 2 9.41 9.40 6.2 4.9 15 31.03 2.88 0.7 0.4 3 11.33 7.81 6.1 4.5 16 34.47 2.60 1.0 1.5 4 14.07 6.29 2.9 2.2 17 35.45 2.53 0.4 0.2 5 14.69 6.03 27.2 17.6 18 37.24 2.41 1.5 0.7 6 17.49 5.07 63.9 100.0 19 38.15 2.36 1.2 0.9 7 19.01 4.67 2.8 1.5 20 40.61 2.22 3.1 2.8 8 21.49 4.13 0.1 0 21 42.83 2.11 1.5 1.4 9 22.11 4.02 12.9 11.2 22 44.89 2.02 1.6 1.3 10 23.17 3.84 19.4 9.5 23 46.01 1.97 2.4 1.8 11 25.91 3.44 3.3 2.5 24 50.36 1.81 0.7 0.8 12 27.41 3.25 31.7 27.4 25 56.63 1.62 1.0 0.9 13 28.31 3.15 19.0 15.1
  2. La forme β-cristalline de pinocembrine selon la revendication 1, caractérisée en ce que la température de décalescence de la courbe de calorimétrie différentielle à balayage, mesurée avec une vitesse de chauffe de 10 °C par minute, est de 204 °C.
  3. La forme β-cristalline de pinocembrine selon la revendication 1, caractérisée en ce que son spectre d'absorption infrarouge contient les pics suivants : 3090.8, 2890.0, 2748.9, 2638.3, 1633.5, 1602.9, 1585.0, 1487.9, 1466.1, 1454.3, 1344.4, 1302.7, 1216.7, 1168.2, 1088.4, 1065.5, 1028.8, 1014.3, 1001.5, 975.8, 917.8, 888.2, 861.8, 826.6, 789.1, 766.6, 741.1, 715.4, 698.0, 663.7, 646.0, 620.5, 587.9, 574.8, 560.9, 527.2 et 488.4 cm1, les pics 2890.0, 2748.9, 2638.3, 1633.5 et 1344.4 cm1 étant les principaux pics caractéristiques de la dite forme β-cristalline de pinocembrine.
  4. Une forme cristalline mixte de pinocembrine consistant en la forme β-cristalline de pinocembrine selon la revendication 1 dans n'importe quelle proportion et une forme α-cristalline de pinocembrine, caractérisée en ce que lorsqu'on l'analyse par diffractométrie de rayons X sur échantillon monocristallin, la forme α-cristalline possède une symétrie de système cristallin monoclinique, le groupe d'espace est P21/c, et les paramètres de la cellule cristalline sont les suivants : a=5.189 Å, b=24.149 Å, c=10.472 Å, α=90 °, β=102.31 ° et γ=90 °.
  5. La forme cristalline de pinocembrine selon l'une des revendications précédentes, caractérisée en ce que la dite forme cristalline ne contient pas d'eau de cristallisation ni d'autre solvant de cristallisation.
  6. Un principe pharmaceutique actif, comportant la forme cristalline de pinocembrine selon la revendication 1 ou 4 en tant que principe actif utilisé dans la fabrication d'un médicament destiné au traitement des maladies liées à l'ischémie cérébrale ou à la prévention des maladies liées à l'ischémie cérébrale par la protection des fonctions du complexe neuro-vasculaire.
  7. Le principe pharmaceutique actif selon la revendication 6, dans lequel le dosage quotidien varie entre 5 et 250 mg, en fonction de la forme cristalline solide de pinocembrine.
  8. Une composition pharmaceutique comportant une quantité thérapeutiquement efficace de la forme cristalline de pinocembrine selon la revendication 1 ou 4, combinée à un ou plusieurs vecteurs pharmaceutiques adaptés.
  9. Une forme galénique comportant le principe pharmaceutique actif selon la revendication 6 ou 7, ou la composition selon la revendication 8, caractérisée en ce que la dite forme galénique est un comprimé, une capsule, une pilule, une injection, une préparation à libération prolongée ou une préparation à libération contrôlée.
  10. La forme cristalline de pinocembrine selon la revendication 1 ou 4, ou le principe pharmaceutique actif selon la revendication 6, ou la composition pharmaceutique selon la revendication 8, destinés au traitement des maladies liées à l'ischémie cérébrale ou à la prévention des maladies liées à l'ischémie cérébrale par la protection des fonctions du complexe neuro-vasculaire.
  11. La forme cristalline de pinocembrine selon la revendication 1 ou 4, ou le principe pharmaceutique actif selon la revendication 6, ou la composition pharmaceutique selon la revendication 8, destinés aux thérapies visant à améliorer la concentration sanguine en pinocembrine dans un organisme grâce à l'effet de la forme cristalline.
  12. Une méthode de préparation d'une forme β-cristalline de pinocembrine, comportant les étapes suivantes :
    utilisation d'une forme cristalline de pinocembrine comme matière première, puis obtention de la forme β-cristalline de pinocembrine selon la revendication 1 par transition cristalline par broyage.
  13. Une méthode de préparation d'une forme β-cristalline de pinocembrine, comportant les étapes suivantes :
    Utilisation d'un échantillon de pinocembrine comme matière première, puis obtention de la forme β-cristalline de pinocembrine selon la revendication 1 par dissolution complète de la matière première dans un solvant de pyridine ou de dyméthylsulfoxyde,
    ajout d'eau pour permettre la précipitation, et filtrage sous pression réduite, lyophilisation ou projection à froid.
EP08878072.1A 2008-11-13 2008-11-13 Deux types de forme cristalline de pinocembrine : a et b, leur préparation et leur utilisation pour la fabrication de compositions pharmaceutiques Not-in-force EP2360152B8 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2008/073047 WO2010054512A1 (fr) 2008-11-13 2008-11-13 Deux types de forme cristalline de pinocembrine : α et β, leur préparation et leur utilisation pour la fabrication de compositions pharmaceutiques

Publications (4)

Publication Number Publication Date
EP2360152A1 EP2360152A1 (fr) 2011-08-24
EP2360152A4 EP2360152A4 (fr) 2012-05-30
EP2360152B1 true EP2360152B1 (fr) 2014-04-09
EP2360152B8 EP2360152B8 (fr) 2014-06-11

Family

ID=42169590

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08878072.1A Not-in-force EP2360152B8 (fr) 2008-11-13 2008-11-13 Deux types de forme cristalline de pinocembrine : a et b, leur préparation et leur utilisation pour la fabrication de compositions pharmaceutiques

Country Status (17)

Country Link
US (1) US8399511B2 (fr)
EP (1) EP2360152B8 (fr)
JP (1) JP5608666B2 (fr)
KR (1) KR101646805B1 (fr)
AP (1) AP2943A (fr)
AU (1) AU2008364170B2 (fr)
BR (1) BRPI0823286A2 (fr)
CA (1) CA2743618C (fr)
CU (1) CU24127B1 (fr)
EA (1) EA020224B1 (fr)
ES (1) ES2476615T3 (fr)
HK (1) HK1160117A1 (fr)
IL (1) IL212849A0 (fr)
MX (1) MX2011005024A (fr)
UA (1) UA102871C2 (fr)
WO (1) WO2010054512A1 (fr)
ZA (1) ZA201104276B (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056188A1 (fr) * 2005-11-04 2007-05-18 President And Fellows Of Harvard College Synthese d'inhibiteurs de ftfz

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1285334C (zh) 2004-05-12 2006-11-22 中国医学科学院药物研究所 生松素在制备防治神经细胞损伤相关疾病药物中的应用
CN101307044B (zh) 2007-05-16 2012-07-04 中国医学科学院药物研究所 生松素化合物两种晶型和制备方法及在疾病治疗中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056188A1 (fr) * 2005-11-04 2007-05-18 President And Fellows Of Harvard College Synthese d'inhibiteurs de ftfz

Also Published As

Publication number Publication date
CA2743618C (fr) 2016-01-26
JP2012508694A (ja) 2012-04-12
CU24127B1 (es) 2015-08-27
EP2360152A4 (fr) 2012-05-30
HK1160117A1 (en) 2012-08-10
AP2943A (en) 2014-07-31
US8399511B2 (en) 2013-03-19
KR101646805B1 (ko) 2016-08-08
CA2743618A1 (fr) 2010-05-20
EP2360152B8 (fr) 2014-06-11
IL212849A0 (en) 2011-07-31
EP2360152A1 (fr) 2011-08-24
EA201170665A1 (ru) 2011-12-30
EA020224B1 (ru) 2014-09-30
MX2011005024A (es) 2011-08-17
UA102871C2 (uk) 2013-08-27
KR20110082599A (ko) 2011-07-19
JP5608666B2 (ja) 2014-10-15
US20110213024A1 (en) 2011-09-01
AP2011005753A0 (en) 2011-06-30
AU2008364170B2 (en) 2014-06-26
ZA201104276B (en) 2012-02-29
WO2010054512A1 (fr) 2010-05-20
BRPI0823286A2 (pt) 2015-06-16
ES2476615T3 (es) 2014-07-15
CU20110104A7 (es) 2012-01-31
AU2008364170A1 (en) 2010-05-20

Similar Documents

Publication Publication Date Title
CN111205332A (zh) 奥沙利铂-黄酮药物共晶及其制备方法和应用
CN112745323B (zh) 枸橼酸爱地那非晶型h及其制备方法和用途
EP4234532A1 (fr) Tétrahydrochlorure de trientine et procédé de préparation et composition pharmaceutique de celui-ci
CN101896477B (zh) 硝克柳胺化合物晶v型、其制法和其药物组合物与用途
CN102846600A (zh) 一种奥拉西坦药物活性组合物及其制备方法
KR20190010578A (ko) 새로운 다파글리플로진 결정형 및 그의 제조 방법 및 용도
CN110437255B (zh) 一种吲哚生物碱或其药学上可接受的盐及制备方法和应用、吲哚生物碱药物组合物及其应用
EP2360152B1 (fr) Deux types de forme cristalline de pinocembrine : a et b, leur préparation et leur utilisation pour la fabrication de compositions pharmaceutiques
WO2004076460A1 (fr) Procede de preparation d'un polymorphisme de chlorhydrate d'irinotecane
CN112592328B (zh) 草豆蔻中二芳基庚烷-查尔酮聚合物及其药物组合物与应用
CN113214209A (zh) 橙皮素与卡马西平共晶物及制备方法和其组合物与用途
CN101463055B (zh) 一类o-糖苷化合物、其制备方法和用途
CN113214207A (zh) 橙皮素与甜菜碱共晶物a及制备方法和其组合物与用途
CN101307044B (zh) 生松素化合物两种晶型和制备方法及在疾病治疗中的应用
CN110483515B (zh) 依波加生物碱或其药学上可接受的盐以及制备方法和应用、依波加生物碱药物组合物及应用
CN101684103B (zh) 1,2,4-三唑结构的化合物、其制备方法和用途
CN115477647A (zh) 小檗碱富马酸盐晶型及其制备方法和其组合物与应用
CN115572292A (zh) 小檗碱丁二酸盐晶型及其制备方法和其组合物与应用
CN118290384A (zh) 大豆苷元与哌嗪共晶物及制备方法和其组合物与用途
CN115536654A (zh) 小檗碱橙皮素盐晶型及其制备方法和其组合物与应用
CN115477646A (zh) 小檗碱柚皮素盐晶型及其制备方法和其组合物与应用
CN111925294A (zh) 一种托特罗定帕莫酸盐及其制备方法
CN114681465A (zh) 洛铂-黄酮药物共晶及其制备方法和应用
AU2023223350A1 (en) Trientine tetrahydrochloride, and preparation method therefor and composition thereof
CN115124419A (zh) 大黄酸与金雀花碱共晶物及制备方法和其组合物与用途

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110614

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/353 20060101ALI20120418BHEP

Ipc: A61P 9/10 20060101ALI20120418BHEP

Ipc: C07D 311/22 20060101AFI20120418BHEP

Ipc: C07D 311/32 20060101ALI20120418BHEP

A4 Supplementary search report drawn up and despatched

Effective date: 20120502

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1160117

Country of ref document: HK

17Q First examination report despatched

Effective date: 20130123

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20131004

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF ME

Owner name: CSPC ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUA

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: AT

Ref legal event code: REF

Ref document number: 661302

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140415

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF ME

Owner name: CSPC ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUA

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602008031471

Country of ref document: DE

Effective date: 20140522

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2476615

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20140715

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 661302

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140409

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20140409

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1160117

Country of ref document: HK

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140709

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140709

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140710

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140809

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140811

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602008031471

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20150112

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602008031471

Country of ref document: DE

Effective date: 20150112

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141113

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141130

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141130

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141113

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20081113

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140409

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20171130

Year of fee payment: 10

Ref country code: DE

Payment date: 20171116

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20171227

Year of fee payment: 10

Ref country code: GB

Payment date: 20171121

Year of fee payment: 10

Ref country code: IT

Payment date: 20171116

Year of fee payment: 10

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602008031471

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20181113

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181130

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190601

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181113

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181113

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20200103

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181114